Where Will New Pain Drugs Come From?

Where Will New Pain Drugs Come From?

The 11th Annual Pain and Migraine Therapeutics Summit, chaired by William Schmidt, NorthStar Consulting, Davis, US, and organized by Arrowhead Publishers and Conferences was held September 27-28, 2017, in San Diego, US. The following is a summary of selected talks presented at the meeting of about 100 researchers from academia as well as from pharmaceutical and biotech companies.

Schmidt began customarily by showing a list of new medications approved by the US Food and Drug Administration (FDA) for pain conditions. The list often contains a dozen new drugs (many of which are simply new formulations of existing drugs, or old drugs approved for new conditions), but this year had only two spots: one for a narrow indication of painful intercourse, and the other an abuse-deterrent opioid formulation. “For the past year—that’s it!” Schmidt said. “Where will the new drugs come from?”

The current epidemic of opioid misuse and abuse is the result, Schmidt said, of “the right tools not being in the right hands—being in the wrong hands.” The silver lining to the crisis may be renewed attention to pain research and treatment. The mission of the meeting, he said, is to change the way pain medicine is practiced, looking beyond current treatments.

The latest on Nav1.7

The voltage-gated sodium channel Nav1.7 is a key player in pain signaling (see RELIEF related feature article), and since both loss- and gain-of-function mutations in SCN9A, the gene for Nav1.7, cause pain disorders, Nav1.7 has been targeted by several companies. Simon Tate, Convergence Pharmaceuticals, Cambridge, UK, a subsidiary of Biogen, reported on a recently completed Phase 2a clinical trial of a small molecule aimed at Nav1.7 for trigeminal neuralgia and other chronic neuropathic pain states. The study was published earlier this year in Lancet Neurology (Zakrzewska et al., 2017).

Trigeminal neuralgia is a rare, debilitating condition that causes excruciating facial pain. Only the sodium-channel blocker carbamazepine is approved by the FDA to treat trigeminal neuralgia, but many patients have trouble tolerating the drug. In addition, “40 to 50 percent of patients with trigeminal neuralgia are prescribed opioids, even though we know they don’t help,” Tate said in his presentation.

The double-blind, multicenter study ultimately included 29 patients randomized to receive an oral dose of either the Convergence Nav1.7 blocker BIIB074 or placebo. “We took the patients off carbamazepine prior to dosing. They were all having attacks—so essentially they were refractory to the drug anyway,” Tate said.

The primary endpoint of the study was treatment failure that resulted in a patient’s withdrawal from treatment. (The criteria for withdrawal included having more than three attacks within seven days; a 50 percent increase in frequency or severity of attacks; or an adverse event that warranted withdrawal.) After four weeks of treatment, about one-third of patients on BIIB074 (33 percent) had treatment failure compared to nearly two-thirds (64 percent) on placebo, but the difference was not statistically significant. The number of painful attacks was cut in half in 60 percent of patients on BIIB074 compared with 21 percent in those on placebo. Pain severity and daily pain scores were decreased by 50 percent in about half of patients on the drug compared to only two of 14 patients on placebo. “Those responses were very significant for the patients after being refractory to carbamazepine,” Tate said.

Schmidt commented after Tate’s talk, “The primary endpoint failed, but you hit everything else. I’d call it a success. It’s clear that this drug has a tremendous benefit for these patients.” A new drug for trigeminal neuralgia would be a welcome addition, especially, Schmidt said, because the disorder is associated with a high rate of suicide.

In an effort to better understand how BIIB074 blocks Nav1.7, Tate and colleagues made electrophysiological recordings from rat dorsal root ganglia (DRG) neurons and from human embryonic kidney (HEK) cells expressing human Nav1.7, which showed that the drug works as a use-dependent blocker. “The more active the channel, the more active the drug becomes,” Tate said, according to their unpublished findings. That is, with repeated electrical stimulation of a neuron, the block by BIIB074 grew stronger. Tate speculated that, as a result, the drug may provide “greater block with increased pain network activity,” as might be present in neuropathic pain conditions. In electrophysiological assays, BIIB074 also showed “much more effective block and a better differential profile over carbamazepine,” Tate said, meaning that it was more selective for Nav1.7 over other sodium channels than the older drug was.

Nav1.7 may not turn out to be the wonder-drug target that some hoped it might, but, says Tate, despite some setbacks, the channel “is a great target with some challenges.” Biogen has additional trials in progress and in the works to test BIIB074, now also called raxatrigine, for trigeminal neuralgia and lumbosacral radiculopathy. Other companies are still in the Nav1.7 game as well, including Purdue Pharma, Teva Pharmaceutical Industries, Chromocell, and SiteOne Therapeutics.

New hope for migraineurs

Few lines of research have generated as much excitement as the recent successes of antibodies directed against calcitonin gene-related peptide (CGRP) or the main CGRP receptor for treatment of migraine (Ho et al., 2010; Tso and Goadsby, 2017; also see RELIEF related article and PRF related webinar). Daniel Mikol, Amgen, Thousand Oaks, US, presented the company’s recent progress with erenumab, a human antibody aimed at the CGRP receptor.

Although it remains unknown exactly how CGRP contributes to migraine, a substantial body of research has shown that the small neuropeptide is released during migraine, can trigger migraine, and that CGRP receptor antagonists can prevent it.

Mikol presented updates on Amgen’s placebo-controlled trials with erenumab in migraine prevention, of which four have been completed—three in episodic migraine and one in chronic migraine. Erenumab was tested in chronic migraine in a double-blind, placebo-controlled Phase 2 trial published in June in Lancet Neurology (Tepper et al., 2017). Chronic migraine is defined as 15 or more total headache days per month, with at least eight of those being migraine days. The 676 randomized subjects received a subcutaneously administered placebo, or 70 or 140 mg of erenumab once every four weeks for 12 weeks.

The study met the primary endpoint of reduced migraine days in the final four weeks compared to baseline. Those receiving placebo saw 4.2 fewer monthly migraine days after treatment, whereas those on either dose of erenumab saw a 6.6-day reduction. When the researchers accounted for the placebo response, the drug provided an additional reduction of 2.5 days. “Forty to 41 percent of patients on the drug experienced at least a 50 percent reduction in migraine days, compared to 23 percent of patients in the placebo group,” Mikol said in his talk.

Interestingly, Mikol reported that when the researchers analyzed subgroups of patients, they found that the drug had better efficacy in people who had previous treatment failures (due to lack of efficacy or poor tolerability with other preventive medications) than in those who had not. “Patients with two or more treatment failures who got 140 mg of erenumab were 4.2 times more likely than patients who got placebo to achieve at least a 50 percent reduction in monthly migraine days from baseline,” Mikol said. He speculated that those patients with past failures may have had lower expectations from the trial and therefore a lower placebo effect.

Episodic migraine, which affects patients fewer than 15 headache days per month, might also respond to erenumab, according to Amgen’s Phase 2 trial published last year (Sun et al., 2016). The trial includes an ongoing open-label extension (OLE) phase. Of the 472 patients who completed the initial 12-week trial, 383 elected to continue in the OLE and received 70 mg of erenumab every four weeks for at least one year. (The OLE will be available to patients for up to five years.) Over the initial 12-week double-blind phase of the trial, average monthly migraine days (MMD) were reduced from 8.8 to 6.3. A year later at 64 weeks, mean MMD had dropped to 3.7, indicating that erenumab continued to reduce migraine frequency with extended use. Several standardized ratings of migraine pain and disability also declined slightly or were maintained for the year. The antibody’s safety profile was also preserved with extended use. The data were published in July in Neurology (Ashina et al., 2017).

In each of the four placebo-controlled trials in migraine prevention, safety profiles were similar between placebo and erenumab groups, and there was no indication of cardiovascular risk. This is important because, aside from CGRP’s role in migraine pathophysiology, it mediates vasodilation, and, therefore, inhibition of CGRP might in theory pose a cardiovascular risk. Mikol said that across the migraine prevention trials they saw no effect of erenumab on blood pressure, but additional safety studies were conducted to address the theoretical risk. In an unpublished study, when applied directly to isolated human coronary arteries obtained from heart valve organ donors, there was no vasoconstrictive effect of erenumab, while vasoconstriction was observed upon exposure to triptans or ergotamines. Further, results of an unpublished treadmill study of patients with ischemic heart disease and stable angina showed that erenumab had no effect on exercise capacity during an exercise treadmill test as measured by total exercise time, a surrogate of myocardial ischemia.

The CGRP antibody beat goes on: Just before this article went to press, positive results from a Phase 3 clinical trial of erenumab for episodic migraine were published in the New England Journal of Medicine (Goadsby et al, 2017; also see related editorial by Hershey, 2017). The study found that a dose of 70 or 140 mg of the drug was superior to placebo in reducing the mean number of migraine days per month, the primary endpoint of the study, over a four- to six-month period. Significant improvement in daily activities and in the use of acute migraine-specific medication was also observed. Comparable rates of adverse events were seen between drug and placebo groups.

In the same issue of NEJM, successful results from a Phase 3 clinical trial of another CGRP-targeted therapy, fremanezumab (from Teva Pharmaceutical Industries), for prevention of chronic migraine were also reported (Silberstein et al., 2017; also see related editorial by Hershey, 2017, as well as previous work on this drug here and here). This human monoclonal antibody targets CGRP itself.

Tools of the trade

Several presenters shared new tools used in various aspects of pain research, all aimed at closing the gap between research success in preclinical models and failure in clinical trials.

Andre Ghetti, AnaBios Corporation, San Diego, US, discussed resources available from the company—namely, neurons from human DRG (see PRF related news story). Researchers can procure the neurons from AnaBios, which harvests them from human organ donors, or they can commission the company to perform electrophysiological and other assays on the cells. AnaBios also makes use of more high-throughput assays such as electrical field stimulation of hundreds of neurons at once, using calcium-indicator dyes as a readout.

The human DRG neurons, Ghetti said, have great predictive value for development of pharmaceutical agents. For example, one compound—an unnamed sodium channel blocker—showed promise in rodents, halting firing of action potentials in DRG neurons and reversing hypersensitivity in vivo. But the compound had no effect on human DRG neurons, even though the target molecule was present, effectively ending further advancement of the compound (and potentially saving time and money developing it). On the flipside, a different sodium channel blocker was “resurrected.” “It was ineffective in cells or in vivo in animals, but in human DRG it was effective at action potential inhibition.” Without that experiment, Ghetti said, “it would have been terminated, but it is now in development.”

While most of AnaBios' experiments so far have involved DRG neurons from pain-free donors, Ghetti said that the company has begun to investigate neurons from people with chronic pain, which make up about 20 percent of their donors. Ghetti said differences have already emerged. “For example, from a patient with fibromyalgia, the neurons were very active spontaneously in the dish—that’s not typical” of neurons from pain-free donors. Such neurons might be used to test compounds that could quiet that spontaneous activity.

Geert Jan Groeneveld, from the Centre for Human Drug Research (CHDR), an independent clinical drug research institute in Leiden, the Netherlands, described PainCart, a comprehensive battery of pain tests contained in a single mobile unit and equipped with software to record test results. PainCart tests include various stimuli to gauge pain, including electrical stimulation in staircase and burst patterns, pneumatic pressure, cold pressor, conditioned pain modulation, thermal heat stimulation, and the ultraviolet B (UVB) irradiation model, which together activate the major classes of C-fiber neurons, Groeneveld said in his talk.

Each analgesic compound has its own signature profile with respect to effects on the PainCart battery of tests, and for each compound, that signature is reproducible over multiple studies. A drug’s effects on responses to any given test in the battery can be explained by the compound’s mechanism of action. As a result, Groeneveld said, the PainCart could be used to help guide drug development by comparing the profile of a new compound to those of established pain-relieving opioid and non-opioid drugs such as fentanyl, ibuprofen, and pregabalin. For example, the Pfizer Nav1.7 blocker PF-05089771, which has had only marginal efficacy in clinical tests, also failed to have an impact on PainCart tests. Conversely, the GABA receptor modulator PF-06372865 showed robust responses similar to pregabalin, which was also predicted based on a comparable site of action in the spinal cord. “The tests look different, depending on the mechanism,” Groeneveld said.

Going deeper

Presenting another tool to aid in predicting the analgesic potential of new compounds was Mikhail (Mike) Nemenov, Stanford University, Palo Alto, US, who serves as president of LasMed LLC. Called diode laser fiber type selective stimulator (DLss) quantitative sensory testing (QST), this tool allows for thermal testing of pain fibers in deeper layers of the skin and even for differentiation of various fiber types and their responses to potential analgesics (Moeller-Bertram et al., 2013).

Currently, heat stimuli used in QST and microneurography—such as a CO2 laser, radiant heat, or a contact thermode—heat the superficial surface of the skin, activating both A-delta and C-fibers in the epidermis. But the heat required to activate deeper C-fiber nerves—which have a slightly higher heat threshold than C-fiber mechano-heat (CMH) neurons—requires surface heating that is exceedingly painful and potentially damaging. The diode laser radiation, however, can penetrate two to three millimeters into the skin, simultaneously heating superficial and deep neurons, Nemenov said.

Nemenov argued that many drugs fail in clinical trials despite preclinical success because the tests used to gauge a compound’s effectiveness are inappropriate in that they can only test the effects on surface CMH neurons. For example, mechanical allodynia is commonly measured in preclinical models of diabetic neuropathy, and yet 40 percent of patients with painful diabetic neuropathy report spontaneous pain without mechanical allodynia, and only 9 percent report allodynia as their primary complaint (Baron et al., 2009). A 2012 microneurography study found that both polymodal C-fibers (CMHs) and, to a greater degree, so-called “silent” mechanically insensitive C-fibers (CMi) were spontaneously active or sensitized in patients with painful diabetic neuropathy to a much greater degree than in patients without pain (Kleggetveit et al., 2012). And microneurographic experiments have shown that, whereas CMH fibers outnumber CMi fibers by two to one in healthy skin, the ratio was flipped in people with diabetic neuropathy (Orstavik and Jørum, 2010). Nemenov said that with neuropathy, the surface CMH fibers retract, accounting for the common symptom of decreased pain sensitivity, whereas the evidence suggests that the deeper CMi fibers mediate the spontaneous pain that patients with diabetic and other peripheral neuropathies complain of. To be effective for painful diabetic neuropathy, Nemenov said, “medications must work on CMi fibers, and they must be proven to work on CMi fibers.”

The DLss laser can achieve that, Nemenov said, thanks to the nerve anatomy in the skin: CMH fibers mainly populate the epidermal layer, whereas CMi fibers are typically found in the sub-epidermis and dermis. Because the DLss laser simultaneously heats superficial and deep layers, the CMi fibers can be safely stimulated and assessed. In addition, by cooling the surface of the skin before using the laser—which has the effect of temporarily silencing A-delta and CMH fibers there—researchers can selectively activate CMi fibers alone, thereby reducing the pain of stimulation, Nemenov said.

Another histological quirk makes it possible to see activation of CMi nerves: They alone mediate the red flare reaction that follows a painful burn, making flare a readout of CMi activity (Schmelz et al., 2000). By using the lowest possible stimulation with the DLss, Nemenov showed in healthy subjects that the laser could activate CMi fibers—as evident from the flare—at levels below subjects’ pain thresholds. The work is unpublished but was presented at the Society for Neuroscience annual meeting in 2016 and in 2017.

Ultimately, Nemenov said, the diode laser can be used to guide go/no-go decisions in drug development by testing, for example, whether an agent could silence or reduce firing of sensitized CMi or CMH fibers, and whether an agent would spare the function of A-delta fibers that are key to acute pain sensation. Because the stimulus may be given repeatedly, it could also be used to test dose escalation over time. Nemenov emphasized in a later conversation with PRF that the ability to test compounds’ effects on the deeper CMi fibers so important in neuropathic pain conditions should improve the quality of drug candidates that progress into large studies.

To conclude the meeting, Schmidt thanked the audience for participating in what he called “a labor of love,” aimed at developing “safer, better, less dangerous treatments for pain.”

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.